Opioid receptors are the receptors to which drugs having morphine-like action specifically bind, and they are found in the central nervous system or intestinal nervous system. Opioid receptors are known to include the three types of μ, δ and κ, where the primary structure of each receptor has been elucidated by cDNA cloning (Wang J-B, FEBS Lett, 338: 217-222, 1994, Simonin F, Mol Pharmacol, 46: 1015-1021, 1994, Simonin F, Proc Natl Acad Sci USA, 92: 7006-7010, 1995). Pharmacological activities of these opioid receptors differ, depending on the types of receptors (Martin W R, J Pharmacol Exp Ther. 197: 517-532, 1976). The μ receptors are involved in analgesia, respiratory depression, euphoria, psychosomatic dependence, tolerance, enterokinesis depression, bradycardia, constipation, miosis, etc. On the other hand, the δ receptors are involved in analgesia, psychosomatic dependence, emotional reaction, etc. The κ receptors are involved in analgesia, sedation, euphoria, diuresis, aversion, miosis, etc.
Morphine is a representative μ receptor agonist (Wood P L, Neuropharmacology, 20: 1215-1220, 1981) and it has been used for those patients with carcinomatous pain or postoperative pain as a potent analgesic. However, morphine exerts analgesic activity, while it causes side effects such as constipation, nausea/emesis, drowsiness, hallucination/obfuscation, respiratory depression, xerostomia/mouth dryness, perspiration, itch, dysuria, unsteadiness/dizziness, and myoclonus. Of these side effects, constipation, nausea/emesis may frequently appear, and itch is also very frequently observed in intrathecal or epidual administration (Guidelines for Alleviation of Carcinomatous Pain, Ed. by the Alleviation Medical Society of Japan, “the Committee for Drafting Guidelines for Alleviation Carcinomatous Pain”, Department of Publication of Medical Books, SINKO-SYUPPAN KOUEKI Co., Ltd., 68-78, 2000).
Opioid peptide is a generic name for the peptide group having morphine-like action and binding to opioid receptors, and the opioid peptides found in the central nervous system and peripheral tissues (intestine, adrenal gland, etc.) are referred to as “endogenous opioid peptides.” β-Endorphin, enkephalin and dynorphin are known as endogenous opioid peptides. Of these peptides, β-endorphin and enkephalin have affinity to μ receptors (Opioid Peptides, Ed. by Hiroo IMURA, CHYUGAI IGAKU Co., Ltd., 240-250, 1985). It has also been reported that production and release of these endogenous opioid peptides are stimulated under various stress environments (in Enkephalins and Endoephins, Ed. by Plotnikoff N P, Plenum, 1986). This has pointed out that endogenous opioid peptides may be a pathogenic cause of idiopathic constipation, postoperative ileus, paralytic ileus, irritable bowel syndrome, chronic pruritus, etc. (Orwoll E S, Endocrinology, 107: 438-442, 1980, Konturek S J, Am J Physiol, 238: G384-G389, 1980, Yamaguchi T, Jpn J Pharmacol, 78: 337-343, 1998).
It is, therefore, believed that the μ receptor antagonists are effective against side effects which are caused by the μ receptor agonists, such as constipation, nausea/emesis, and itch, or diseases such as idiopathic constipation, postoperative ileus, paralytic ileus, irritable bowel syndrome and chronic pruritus.
According to Japanese Patent Kokai No. 264460/1988 (JP-A-63264460), a drug having the action of reversing respiratory depression, one of side effects of morphine, that is, an opioid μ receptor antagonist has been identified as the compound of the formula (XI), which is an analogous compound originated from fentanyl, an opioid μ receptor agonist.
However, the opioid μ receptor antagonistic activity of this drug is weak and insufficient as a therapeutic agent for imperfect enterokinesis such as constipation and irritable bowel syndrome. Therefore, there has been a need for more potent opioid μ receptor antagonists.